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Synthesis, structure optimization and antifungal screening of novel tetrazole ring bearing acyl-hydrazones.

Malik MA, Al-Thabaiti SA, Malik MA - Int J Mol Sci (2012)

Bottom Line: Propidium iodide rapidly penetrated a majority of yeast cells when they were treated with the synthesized compounds at concentrations just above MIC, implying that fungicidal activity resulted from extensive lesions of the plasma membrane.Target compounds also caused a considerable reduction in the amount of ergosterol.The results also showed that the presence and position of different substituents on the phenyl ring of the acylhydrazone pendant seem to play a role on the antifungal activity as well as in deciding the fungistatic and fungicidal nature of the compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21413, Saudi Arabia; E-Mail: sthabaiti@kau.edu.sa.

ABSTRACT
Azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. In an attempt to find novel azole antifungal agents with improved activity, a series of tetrazole ring bearing acylhydrazone derivatives were synthesized and screened for their in vitro antifungal activity. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and determination of the levels of ergosterol, a fungal-specific sterol. Propidium iodide rapidly penetrated a majority of yeast cells when they were treated with the synthesized compounds at concentrations just above MIC, implying that fungicidal activity resulted from extensive lesions of the plasma membrane. Target compounds also caused a considerable reduction in the amount of ergosterol. The results also showed that the presence and position of different substituents on the phenyl ring of the acylhydrazone pendant seem to play a role on the antifungal activity as well as in deciding the fungistatic and fungicidal nature of the compounds.

No MeSH data available.


Related in: MedlinePlus

UV spectrophotometric sterol profiles of representative resistant Candida isolates. Isolates were grown for 16 h in sabouraud dextrose broth containing 0 (curve a), ½ MIC’s of compounds—TH1 (curve b), TH2 (curve c), TH3 (curve d), TH4 (curve e), TH5 (curve f), TH6 (curve l), TH7 (curve m), TH8 (curve n), TH9 (curve o), TH10 (curve p) or MIC’s of compounds—TH1 (curve g), TH2 (curve h), TH3 (curve i), TH4 (curve j), TH5 (curve k), TH6 (curve q), TH7 (curve r), TH8 (curve s), TH9 (curve t), TH10 (curve u) or 64 mg of fluconazole per liter (curve v). Sterols were extracted from cells, and spectral profiles between 240 and 300 nm were determined. X-axis represents the wavelength between 240 nm and 300 nm.
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f3-ijms-13-10880: UV spectrophotometric sterol profiles of representative resistant Candida isolates. Isolates were grown for 16 h in sabouraud dextrose broth containing 0 (curve a), ½ MIC’s of compounds—TH1 (curve b), TH2 (curve c), TH3 (curve d), TH4 (curve e), TH5 (curve f), TH6 (curve l), TH7 (curve m), TH8 (curve n), TH9 (curve o), TH10 (curve p) or MIC’s of compounds—TH1 (curve g), TH2 (curve h), TH3 (curve i), TH4 (curve j), TH5 (curve k), TH6 (curve q), TH7 (curve r), TH8 (curve s), TH9 (curve t), TH10 (curve u) or 64 mg of fluconazole per liter (curve v). Sterols were extracted from cells, and spectral profiles between 240 and 300 nm were determined. X-axis represents the wavelength between 240 nm and 300 nm.

Mentions: Table 3 summarizes the effect of the test compounds on ergosterol biosynthesis in different fluconazole-sensitive and fluconazole-resistant Candida isolates. The total ergosterol content was determined for each isolate grown in ½ MIC and MIC values of all the test compounds. A dose-dependent decrease in ergosterol production was observed when isolates were grown in the presence of test compounds (Figures 2 and 3).


Synthesis, structure optimization and antifungal screening of novel tetrazole ring bearing acyl-hydrazones.

Malik MA, Al-Thabaiti SA, Malik MA - Int J Mol Sci (2012)

UV spectrophotometric sterol profiles of representative resistant Candida isolates. Isolates were grown for 16 h in sabouraud dextrose broth containing 0 (curve a), ½ MIC’s of compounds—TH1 (curve b), TH2 (curve c), TH3 (curve d), TH4 (curve e), TH5 (curve f), TH6 (curve l), TH7 (curve m), TH8 (curve n), TH9 (curve o), TH10 (curve p) or MIC’s of compounds—TH1 (curve g), TH2 (curve h), TH3 (curve i), TH4 (curve j), TH5 (curve k), TH6 (curve q), TH7 (curve r), TH8 (curve s), TH9 (curve t), TH10 (curve u) or 64 mg of fluconazole per liter (curve v). Sterols were extracted from cells, and spectral profiles between 240 and 300 nm were determined. X-axis represents the wavelength between 240 nm and 300 nm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472718&req=5

f3-ijms-13-10880: UV spectrophotometric sterol profiles of representative resistant Candida isolates. Isolates were grown for 16 h in sabouraud dextrose broth containing 0 (curve a), ½ MIC’s of compounds—TH1 (curve b), TH2 (curve c), TH3 (curve d), TH4 (curve e), TH5 (curve f), TH6 (curve l), TH7 (curve m), TH8 (curve n), TH9 (curve o), TH10 (curve p) or MIC’s of compounds—TH1 (curve g), TH2 (curve h), TH3 (curve i), TH4 (curve j), TH5 (curve k), TH6 (curve q), TH7 (curve r), TH8 (curve s), TH9 (curve t), TH10 (curve u) or 64 mg of fluconazole per liter (curve v). Sterols were extracted from cells, and spectral profiles between 240 and 300 nm were determined. X-axis represents the wavelength between 240 nm and 300 nm.
Mentions: Table 3 summarizes the effect of the test compounds on ergosterol biosynthesis in different fluconazole-sensitive and fluconazole-resistant Candida isolates. The total ergosterol content was determined for each isolate grown in ½ MIC and MIC values of all the test compounds. A dose-dependent decrease in ergosterol production was observed when isolates were grown in the presence of test compounds (Figures 2 and 3).

Bottom Line: Propidium iodide rapidly penetrated a majority of yeast cells when they were treated with the synthesized compounds at concentrations just above MIC, implying that fungicidal activity resulted from extensive lesions of the plasma membrane.Target compounds also caused a considerable reduction in the amount of ergosterol.The results also showed that the presence and position of different substituents on the phenyl ring of the acylhydrazone pendant seem to play a role on the antifungal activity as well as in deciding the fungistatic and fungicidal nature of the compounds.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21413, Saudi Arabia; E-Mail: sthabaiti@kau.edu.sa.

ABSTRACT
Azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. In an attempt to find novel azole antifungal agents with improved activity, a series of tetrazole ring bearing acylhydrazone derivatives were synthesized and screened for their in vitro antifungal activity. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and determination of the levels of ergosterol, a fungal-specific sterol. Propidium iodide rapidly penetrated a majority of yeast cells when they were treated with the synthesized compounds at concentrations just above MIC, implying that fungicidal activity resulted from extensive lesions of the plasma membrane. Target compounds also caused a considerable reduction in the amount of ergosterol. The results also showed that the presence and position of different substituents on the phenyl ring of the acylhydrazone pendant seem to play a role on the antifungal activity as well as in deciding the fungistatic and fungicidal nature of the compounds.

No MeSH data available.


Related in: MedlinePlus